title: Nanotoxicity comparison of four amphiphilic polymeric micelles with similar hydrophilic or hydrophobic structure.
abstract: BACKGROUND
  Nanocarriers represent an attractive means of drug delivery, but their biosafety must be established before their use in clinical research.
  
  
  OBJECTIVE
  Four kinds of amphiphilic polymeric (PEG-PG-PCL, PEEP-PCL, PEG-PCL and PEG-DSPE) micelles with similar hydrophilic or hydrophobic structure were prepared and their in vitro and in vivo safety were evaluated and compared.
  
  
  METHODS
  In vitro nanotoxicity evaluations included assessments of cell morphology, cell volume, inflammatory effects, cytotoxicity, apoptosis and membrane fluidity. An umbilical vein cell line (Eahy.926) and a kind of macrophages (J774.A1) were used as cell models considering that intravenous route is dominant for micelle delivery systems. In vivo analyses included complete blood count, lymphocyte subset analysis, detection of plasma inflammatory factors and histological observations of major organs after intravenous administration to KM mice.
  
  
  RESULTS
  All the micelles enhanced inflammatory molecules in J774.A1 cells, likely resulting from the increased ROS levels. PEG-PG-PCL and PEEP-PCL micelles were found to increase the J774.A1 cell volume. This likely correlated with the size of PEG-PG-PCL micelles and the polyphosphoester structure in PEEP-PCL. PEG-DSPE micelles inhibited the growth of Eahy.926 cells via inducing apoptosis. This might relate to the structure of DSPE, which is a type of phospholipid and has good affinity with cell membrane. No evidence was found for cell membrane changes after treatment with these micelles for 24 h. In the in vivo study, during 8 days of 4 time injection, each of the four nanocarriers altered the hematic phase differently without changes in inflammatory factors or pathological changes in target organs.
  
  
  CONCLUSIONS
  These results demonstrate that the micelles investigated exhibit diverse nanotoxicity correlated with their structures, their biosafety is different in different cell model, and there is no in vitro and in vivo correlation found. We believe that this study will certainly provide more scientific understandings on the nanotoxicity of amphiphilic polymeric micelles.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. wangxq@bjmu.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.forename: Xue-Qing
authors.initials: XQ
authors.lastname: Wang
authors.forename: Xiao-You
authors.initials: XY
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Wen-Bing
authors.initials: WB
authors.lastname: Dai
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Zhen-Lin
authors.initials: ZL
authors.lastname: Zhong
authors.forename: Hou-Nan
authors.initials: HN
authors.lastname: Wu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D004337:Drug Carriers / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D008823:Micelles; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D009928:Organ Specificity; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013499:Surface Properties; D013501:Surface-Active Agents / Q000737:chemistry / Q000633:toxicity*; D018675:Toxicity Tests
chemical_list: D016207:Cytokines; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D017382:Reactive Oxygen Species; D013501:Surface-Active Agents; D011092:Polyethylene Glycols